Peptide-based targeted cancer therapeutics: Design, synthesis and biological evaluation

kinases play a fundamental role in transducing various signals that control proliferation, survival, migration andinvasion in several cancers such as Chronic Myeloid Leukemia (CML), breast cancer and brain cancer. For thesereasons Abl tyrosine kinases are considered important biological targets in drug discovery. In this study a seriesof lysine-based oligopeptides with expected Abl inhibitory activity were designed resembling the binding of FDAapproveddrugs (i.e. of Imatinib and Nilotinib), synthesized, purified by High Performance Liquid Chromatography(HPLC), analyzed by mass spectrometry (MS) and biologically tested in vitro in CML (AR-230 and K-562),breast cancers (MDA-MB 231 and MDA-MB 468) and glioblastoma cell lines (U87 and U118). The solid-phasepeptide synthesis (SPPS) by Fmoc (9-fluorenylmethoxycarbonyl) chemistry was used to synthesize target compounds.AutoDock Vina was applied for simulation binding to Abl. The biological activities were measuredevaluating cytotoxic effect, induction of apoptosis and inhibition of cancer cells migration. The new peptidesexhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 72 htreatment. The most promising results were obtained with the U87 glioblastoma cell line where a significantreduction of the migration ability was detected with one compound (H-Lys1-Lys2-Lys3-NH2).